Scalable Self-Assembling Micellar System for Enhanced Oral Bioavailability and Efficacy of Lisofylline for Treatment of Type -I Diabetes

The study summarizes the development of an orally active nanoformulation of a potent but one of the least explored molecules, lisofylline (LSF), in type 1 diabetes (T1D). LSF undergoes rapid metabolism, resulting in poor oral bioavailability and short half-life. In this work, to improve its pharmacokinetic (PK) properties, LSF was encapsulated in the form of its ester prodrug [LSF- linoleic acid (LA) prodrug] into biodegradable self-assembling polymeric micelles [LSF-LA PLM, size: 149.3 nm; polydispersity index: 0.209; critical micelle concentration (cmc); 5.95 mu g/mL and N-agg: 14.82 at 10 cmc] of methoxypoly(ethylene glycol)-b-poly(carbonate-co-L-lactide) (mPEG-b-P(CB-co-LA)) block copolymer. LSF-LA PLM was found to be equally effective as the LSF LA prodrug in cell culture studies in insulinsecreting MINE cells and showed excellent stability in simulating biological fluids and plasma. PK of LSF-LA PLM (10 mg/kg dose) revealed a significant improvement in oral bioavailability of LSF (74.86%; 3.3 -fold increase in comparison to free LSF) and drastic reduction in the drug metabolism. Further, LSF-LA PLM showed a significant reduction in fasting glucose levels and increase in insulin levels by intraperitoneal as well oral routes in a streptozotocin (STZ)-induced T1D rat model. Production of inflammatory cytokines (TNF-alpha and IFN-gamma) and different biochemical markers for liver and kidney functions were much reduced in diabetic animals after treatment with LSF-LA PLM. LSF-LA PLM-treated pancreatic sections showed minimal infiltration of CD4+ and CD8+ T-cells as indicated by hematoxylin/eosin staining and immunohistochemical analysis.